Regional Radiotherapy in Biomarker Low-Risk Node Positive and T3N0 Breast Cancer

Inclusion Criteria:

• Patients must be women with newly diagnosed histologically proven invasive carcinomaof the breast with no evidence of metastases, staged as per site standard of care.

• Patients must have been treated by BCS or mastectomy with clear margins of excision.Post-mastectomy positive margins for invasive disease and/or DCIS is not allowed.Multifocal disease (i.e. the presence of two or more foci or breast cancer withinthe same breast quadrant) and multicentric disease (i.e. the presence of two or morefoci of breast cancer in different quadrants of the same breast) are allowed.

• Patients with T3N0 disease are eligible.

• Patients with disease limited to nodal micrometastases are eligible

• Patients with nodal macrometastases (>2mm) treated by axillary dissection must have 1-3 positive axillary nodes (macrometastases, > 2 mm).

• Patients treated by mastectomy and SLNB alone must have only 1-2 positive axillarynodes (macrometastases, > 2 mm).

• Patients must be ER ≥ 1% and HER2 negative on local testing

• Patients must have an Oncotype DX recurrence score ≤25 obtained from testing ofbreast tumour tissue from a core biopsy or from the surgical specimen.

• Patient must consent to provision of, and investigator(s) must agree to submit tothe CCTG Central Tumour Bank, a representative formalin fixed paraffin block oftumour tissue in order that the specific correlative marker assays described in theprotocol may be conducted

• Patient must consent to provision of samples of blood in order that the specificcorrelative marker assays described in the protocol may be conducted.

• Patients must have had endocrine therapy initiated or planned for ≥ 5 years.Premenopausal women will receive ovarian ablation plus aromatase inhibitor therapyor tamoxifen if adjuvant chemotherapy was not administered. For all patients,endocrine therapy can be given concurrently or following RT.

• Patients may or may not have had adjuvant chemotherapy.

• RT must commence within 16 weeks of definitive surgery if the patient is not treatedwith chemotherapy. If adjuvant chemotherapy is given, RT must begin within 12 weeksafter the last dose. (Note: adjuvant chemotherapy may be ongoing at the time ofrandomization). Definitive surgery is defined as the last breast cancer-relatedsurgery.

• Patient's ECOG performance status must be 0, 1 or 2.

• Patient's age must be ≥ 35 years.

• For the first 736 eligible English or French-speaking subjects who have agreed tooptional questionnaire completion: Patient is able (i.e. sufficiently fluent) andwilling to complete the quality of life, health utilities and lost productivityquestionnaires in either English or French (note: enrollment completed 2022Aug02)

• Patient consent must be appropriately obtained in accordance with applicable localand regulatory requirements

• Patients must be accessible for treatment and follow-up. Investigators must assurethemselves the patients randomized on this trial will be available for completedocumentation of the treatment, adverse events, and follow-up.

• In accordance with CCTG policy, protocol treatment is to begin within 6 weeks ofpatient randomization.

• Women of childbearing potential must have agreed to use an effective contraceptivemethod. A woman is considered to be of "childbearing potential" if she has hadmenses at any time in the preceding 12 consecutive months.

Exclusion Criteria:

• Patients with nodal disease limited to isolated tumour cells (pN0i+ < 0.2 mm).

• Patients with pT3N1 and pT4 disease (Note: patients with T3N0 are eligible).

• Any prior history, not including the index cancer, of ipsilateral invasive breastcancer or ipsilateral DCIS treated with radiation therapy. (Patients withsynchronous or previous ipsilateral LCIS are eligible.)

• Synchronous or previous contralateral invasive breast cancer. (Patients withcontralateral DCIS are eligible unless previously treated with radiation.)

• History of non-breast malignancies except adequately treated non-melanoma skincancers, in situ cancers treated by local excision or other cancers curativelytreated with no evidence of disease for ≥ 5 years.

• Patients who are pregnant.

• Patients that have had prior ipsilateral chestwall/thoracic radiation.

• Patients treated with chemo or endocrine therapy administered in the neoadjuvantsetting for breast cancer. Endocrine therapy exposure 12 weeks or less prior tosurgery is permitted.

• Patients with serious non-malignant disease (e.g. cardiovascular, scleroderma etc.)which would preclude RT.

• Patients with any serious active or co-morbid medical conditions, laboratoryabnormality, psychiatric illness, active or uncontrolled infections, or seriousillnesses or medical conditions that would prevent the patient from participating orto be managed according to the protocol (according to investigator's decision).